Tag Archive: indole


I have been reading through cyclocondensations and multi-step routes to fused ring systems and came across a highlight from Doris Dallinger’s post on the Organic Chemistry Portal. Although a bit older I have always found domino multi-component reactions have a penchant for the dramatic and this example (OL 2008) is no exception. This group, out of Kyoto, utilized a Cu(I) catalyzed 3-component microwave reaction sequence, starting with a Mannich, followed with an indole ring formation at 170C for 20 min. Addition of NaOMe and re-heating in the microwave for an additional 20 min at 170C deprotected and N-Arylated the Indole nitrogen for a short route to mixed-1,4 diazepines. Solvent studies and catalyst loadings were optimized to show dioxane and 2.5%CuI for the protocol. In addition to the benzene ring on the lower portion of the scaffold, additional heterocycles were used to broaden the availability of fused rings….which would tell me that the amine, left-hand or indole substitution and the lower ring system can be varied to include a number of different features as well as additional space to consider from a med chem point of view.

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If the ring system looks slightly familiar or the subject matter, I have posted an indole based domino sequence in the past and if it just happens to be that day, have a look. Happy Reading!

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At first glance this may seem like an extension to the installments (there are 5) on microwave methods toward the construction of indoles — but it has a bit more of a story than that. I found a minireview out of Northeastern University by Graham Jones and Nadeesha Ranasinghe that I posted on my flow chemistry resource blog — mainly because the journal article emphasis both continuous flow, microwave and the combination thereof. So some of the introduction and historical perspective can be found there. For this I will stick closer to the theme: microwave methods and show a few more examples that one can dig into off-line.

Although it would be the place to start – the Fisher Indole synthesis is one of the most published methods around and there are some examples using microwave to speed up the reaction — I think this is one that can be done in a large microwave batch reactor easily. But the emphasis here is on indoles, and their rightful place in the top 2-3 of the heterocyles researched in drug discovery.

The first example shows a movement away from solvent into a solvent-free approach using p-TSA and several enolizable ketones from Horaguchi in J Het Chem 2011.

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In keeping with a similar theme, Barluenga reported (Chem Eur J 2010) a heterogeneous Pd-sequential coupling of arenes to a number of imine starting materials in aqueous media to reduce reaction times from 24-48 hours to 30-60 min in high yield (no organic solvents and sequential steps).

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Moving over to drug targets, Thirupathi Reddy reported (Bioorg Med Chem 2010) an approach to marine natural product mimics of aplysinopsin, with the preparation of indole-2-imidazoline-2,4-diones under microwave heating and a comparison to conventional heating.

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A multi-step combinatorial approach to a library of compounds was reported with indole-2-carboxylic acid, ethyl pyruvate with amines and isocyanides as a four component, 2-step Ugi and subsequent cyclization in TL 2009.

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An approach to antitubercular activity was reported in a library of compounds made in a modified Fisher indole synthesis to 2-aryl-3,4-dihydro-2H-thieno[3,2-b]indoles using microwave heating for 3-6 min at 90C (Biorg Med Chem Lett 2009).

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And we can end on an approach I mentioned in my 4th installment of microwave indole construction, Peter Wipf’s usage of an intramolecular diels alder with a pendant amino furan (IMDAF) as a tandem diels-alder rearrangement sequence to provide an array of substituted indoles under microwave heating (JOC 2013).

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And for those us who enjoy the arrows, you can see the release of H2O in the cycloadduct to form the indole.

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Several examples have been shown where microwave technology has been a key step in the formation of indoles as targets in basic research and in the formation of medicinally important compounds, either in the form of analog libraries or mimics to compounds hitting targets of interest. This certainly indicates to me that we have a number of current approaches to indole targets and microwave synthesis can be used as a tool to rapidly provide compounds for testing or quickly decide the relevance of a target class. I end by pointing back to the minireview as a source of information and inspiration. Happy Reading!

Alternative thinking…….one way to think of deconstructing a heterocycle is to sit down and break the bond forming steps into a spreadsheet of all the known reactions to form them. By now however I am hoping that intuition has crept into the toolbox of things to use…….ask yourself what chemists you know are more intuitive and who are more methodical?

moving on…..Corey Chaykovsky

Following Bill Johnson’s initial work on formation of three membered rings, Corey and Chaykovsky developed the reaction for what it is know today. The scheme below represents the approach: a sulfur ylide (comeon’ man….I love these) and a ketone, imine or an enone.

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Corey Chaykovsky Reaction (CCr)

If you understand anything residual about Prof Corey, you will want to use this from/or for a disconnection. It just so happens that an epoxide attached to an aromatic ring is set up to undergo nucleophilic attack from an amine, and if alpha to that epoxide is a F group, we know that the amine can attack this as well — you see where I am driving at.

In a recent publication on the construction of N-subst indoles (Synthesis 2008), these 3 components were used in a clever way.

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Corey Chayvosky constructed int with amine and elimination of H2O under microwave conditions: ketone, sulfur ylide then amine — indole

Enjoy the reaction!

I am going to go to the left side of the ballpark on this one, because if you like this site, small bits and pieces from several posts will show up. A few hints on this one…..remember, I like indoles, cascades, rearrangements —

This indole construction has its’ bottom seated in the intramolecular diels alder of a furan approach (IMDAF). I tip my hat to start to Al Padwa and Peter Wipf for some elegant construction of indoles without some of our more popular transition-metal catalyzed approaches we know look to pull off the shelves (as Henry Rappaport once said to me, as an organic chemist you should never be seduced by commercial availability — a true test it to make it. OK I love that sort of stuff from the giants.

Indoles from this approach: 3,4 from amino furan IMDAF with appropriately position double bonds and 4,5,6- (but particularly the 5-hydroxy for obvious reasons) from the amino furan and IMDAF and a triple bond (remember above — a furan 2-carboxylic acid undergoes a nice Curtius rearrangement to provide 2-amino furans – now I have 2 microwave steps again, just a game I play).

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3,4-Substituted indoles IMADF

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5-hydroxyindoles

Before moving to the microwave the IMDAF reaction was popularized in the 60s — Wasserman, Cram, Herz were doing these when the music was good. Move forward and Al Padwa put some unbelievable touches on the reaction by placing and amino group on the furan system….I have done some reactions with this pendant group and it really can help open what can be made….anyway I have digressed, and if you are interested in these cyclizations or [4+2] cycloadditions take a look at the monograph series Advances in Cycloadditions.

Chem Comm 2009 in this report, Wipf’s group uses the appropriately positioned allylic alcohol with the amino furan in a microwave.  The process shown below produced moderate to good yields of the 4-substituted indoles, but in comparison to straight thermal conditions which only produced decomposition of the starting material.

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Microwave conditions for IMDAF

You should stay tuned to the first 2 schemes with the alkyne and some development on the amino furan moiety (brief reports from the Wipf team indicate they have made tremendous progress in indole construction with some tandem processes that expand the approach). I can’t wait to read the papers Peter.

 

Maybe it’s just me, but I like the idea of having a functionality that can be used and replaced with another functionality in a reaction. Many rearrangements offer just that and the Curtius rearrangemnt is no exception. Just think about having a nice carboxylic acid on a heterocycle that needs to be a nitrogen — and OK I’m stretching here but a coupling just isn’t cutting it….or maybe you want to replace the acid with a urea moiety. I also like reactions that run downhill so to speak….you know they give up energy easily and in this case nitrogen. Now that I sped ahead, let’s back up and show the scheme below:

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Curtius Rearrangement: Acyl azide to isocyante

So depending on what you want and where you started, it can be a urethane (carbamate), urea or amine. What is most popular is the use of DPPA (diphenylphosphorylazide) to convert the acid to acyl azide.

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Curtius rearrangement from acid to urethane

A recent paper (Tetrahedron 2012) illustrates the utility of a Curtius rearrangement in the synthesis of isocryptolepine (below) using microwave irradiation. The novelty in this approach is that the impending isocyanate is trapped at the 3-position on an indole — wish I had thought of that — tandem Curtius, aza 6(pi) electrocyclization. If you read this blog regularly it should be obvious that the 2-aryl indoles would be a perfect set-up for setting this up….now that’s two microwave steps to generate analogs of this indolo[3,2-c]quinoline alkaloid (folk antimalarial).

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Isocryptolepine

Taking a look at the scheme starting from indole 2, N-MOM protection and hydrolysis set up the requisite carboxylic acid, 3. The acid is simply reacted with DPPA in toluene under microwave irradiation to deliver the desired fused lactam in 97% yield.

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Setting up the Curtius starting material

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Curtius/electrocylization microwave reaction

Although I would probably find use for these as well, protecting groups play a big role in this working. If the protecting group falls off (as is the case with N-BOC) or the indole nitrogen is unprotected, a competing mechanism with formation of the urea on the indole nitrogen takes place. Haha! I love reading papers where the research group has to figure that out — doesn’t it sound like how we really work?

Happy Reading!

Since this is so well known and used so often, I wanted to indicate a few of the modifications that have been used for indole construction, either as a substituted indole itself or as a fused carbazole…..by a Fischer indole ring forming process. Just for a second let’s take a quick look at our organic text book — remember a substituted ketone and a substituted aryl hydrazine will provide the desired heterocycle. Of course the opposite disconnection has been used as well with the advent of the Buchwald amine coupling method. As you would think in an acidic mediated ring closure, most modifications have utilized B&L acids.

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Fischer Indole

Here are a few recent examples:

The Journal of Heterocylic Chemistry (2011)- In this example, the group started by using ZnCl2 to form 1,2,3,4-tetrahydrocarbazole with phenylhydrazine and cyclohexanone in 3 minutes in the microwave (one-pot). Albeit in decent yield, when they switched to p-TsOH (cat)there was a tremendous boost in yield.

Indian Journal of Chemistry Sec B 2011 – In this example, the group screened the ring formation post arylhydrazone formation to examine the efficiency of the acid and also to look at some of the selectivity patterns in the carbazole formation.

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Ring Formation

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Montmorillonite KSF cyclization

Tetrahedron Letters 2011 – In this example, several indoles and carbazoles were synthesized with proylphonic anhydride (T3P) as the acid catalyst. The reaction takes place in minutes with EtOAc as the solvent, indicating that the work for this type of method can be broadened.

Angewendte Chemie 2010 — For those of you looking for a twist and the ability to gain some additional substitution, Knochel’s group will always help you look for organozinc alternatives to traditional methods. In the following example, the group utilized specifically constructed organozinc reagents to couple with susbtituted aryl diazonium salts with a triflate activating group followed by ring formation under microwave irradiation (125C, 30 min) to provide the requisite indole.

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Knochel zinc/indole Fischer modification

There are numerous examples of acid-catalyzed ring formations, modifications of the traditional Fischer process and substitution patterns in the literature that should entice your appetite when there is a need for an indole or carbazole. One of the nice results that comes out of some of this work in the microwave is that there are many starting points to provide a method to use and given the short reaction times, you will have a result promptly. A final example illustates that the ring formation can come in late in a synthesis or as a set-up for additional substitution with a 2-substituted pyridyl indole formation.

Organic Letters 2006 – By choosing a late-stage ketone it is possible to obtain some  substitutions that are otherwise very difficult to obtain through other methods. In this example a methyl ketone on a fused pyridine is set up to react with an aryl hydrazine followed by a microwave induced Fischer indole (ZnCl2/TEG) reaction. And what we learned earlier is that maybe it can even be modified through a little screening effort to be done in a one-pot fashion and show the power of both the Fischer method and improvements in the microwave approach.

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MW Fisher ring closure

Happy Reading! Good to be back!

 

The first installment of cool methods for indole construction seemed to be well received so I thought I would try another (one which I had done in my past). With the ability to C-C triple bonds to aromatic rings, the set-up up for a cycloisomerization reaction of an ortho amine seems like a great way to construct the requisite indole. Looking at the scheme below, there are a few approaches to the connection. For this story we are going to look at route a, but concentrating on the ring formation.

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Disconnection approaches to cyclizations

The general idea for the reaction can be shown from the scheme below (shown from another good book [Catalyzed Carbon Heteroatom Bond Construction late 2010] to get your hands on since it provides strategies for carbon catalyzed heteroatom bond construction, with all the big players). Isn’t that high on your list of needs in synthetic strategies?

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Cu-catalyzed Indole cyclization

Ok without drawing arrows all over the place – the accepted mechanism is generally described as a 5-exo-dig intramolecular cyclization of the amine onto a transition-metal activated C-C multiple bond. Given the simplicity of the reaction and the number of possibilities as starting materials I would say this is a great way to construct the heterocycle late in a scheme if needed. But what I typically look for are the conditions — DMF 110C for 8 h is just way too long nowadays when we have new tools. So let’s blow this up and look at expanding the scope a bit, perhaps a variety of ring substitutions or substituted pyridines for making azaindoles. Ready?

A recent publication from the chemistry development group at GlaxoSmithKline in Italy (Tetrahedron 2010) developed an approach to a variety of the aforementioned varieties from 2-alkynylanilines as well as some pyridine analogs. Now you will have to do some work and read through the paper a bit, but the schemes below indicate a variety of substitutions on the aromatic ring as well as R group at the 2-position of the indole if you will can be varied to include a hydrogen or alkyl functionality — so you are not bound by aromatic groups to get the reaction to go [alkyl and the unsubstituted alkyne will cyclize nicely.

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Cyclization in a closed-vessel with a variety of bases

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Aryl subst – albeit fixed for the closure

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5-Azaindoles

So you can see this group utilized NaHCO3, pyrrolidine and Na2CO3 at 200C for 15-90 minutes to provide the indoles in good to high yields (water based in nearly all cases). There are several additional examples that will help satisfy curiosities and  to look at other examples. One thing to note is that looking back at our initial mechanism of an activated multiple bond by a transition metal — doesn’t look like that is a requisite for constructing the ring and perhaps that gives some thought on additional things to try. Certainly from a development route perspective, I would opt for the non-metal based approach. But I am also certain the metal chemists would give me plenty of reasons they can find a better way. If properly positioned in a total synthesis with the need for an indole ring, at least it can be placed at many different timepoints. Happy Reading!

Maybe you can think of this as a fondness for indoles or if you have read a number of my posts, that I tend to dabble a bit in the construction of heteroaromatic rings…but just a bit, lol! So I decided that next to the reaction of the week I will give an installment of some indole and azaindole construction and perhaps some substitutions to relive my old days.One of the cool things about this ring is that it has been made in so many different ways and with so many patterns it has a place on the top shelf of the heterocycle hall of fame…..we should do the stats and see which ring or fused system has been made the most. OK OK I better get to it. The Hemetsberger indole synthesis is not the most popular of the brands out there but it is an elegantly simple process to use if you can make variations of the starting 3-aryl( or heteroaryl)-2-azido-propenoic ester because upon heating you should generate the 2-carboxylate on the indole nucleus. LOVE IT! what, heat from starting material to product — I can’t think of anything but a microwave. And for those of you who like arrows like I do — watch the energy give off during the reaction. As a side note the vinyl azide is made with an aromatic aldehdye and ethyl azidoacetate condensation. Since it is a thermal process with N2 release most of these have been made with refluxing toluene or xylene.

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Hemetsberger Indole Method

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Reaction mechanism

Application of the process (TL 2009) in the microwave provided the indoles in 10 minutes under microwave conditions. Several substrates indicated the utility of the process but what was most interesting end up being the method screening. Several different solvents were examined for conversion. Note in these cases the best reactions were performed in poor microwave absorbing solvent systems.

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Solvent screening

Another method study involved the temperatures used and pressures developed from the release of N2 during the reaction along with the vapor pressures generated for each solvent. (this is something many chemists don’t keep track of moving from conventional methods over to the microwave — consider the solvent choices and the vapor pressure they can generate at high temperatures — the vessel choice based on that is critical for success).

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A) 200 °C, 15 min, 13.5 bar. (B) 200 °C, 10 min, 13.5 bar. (C) 200 °C (only 136 °C reached), 5 min, 6.2 bar. (D) 150 °C, 10 min, 6.9 bar. (E) 100 °C, 10 min, 4.2 bar

So in the end — 200C in hexanes for 10 min provided the compounds with no side reactions during the process.

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